The field of the invention is positron emission tomography (PET) imaging. More particularly, the invention relates to PET imaging of 63Zn distribution in biological systems (including human) for noninvasive measurement of zinc transport and biodistribution.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting more than 4 million people in the United States. However, the diagnosis and treatment of the disease have been hampered by the absence of reliable noninvasive markers for the underlying pathology. The most developed areas of molecular imaging of AD entails PET imaging of glucose metabolism using [18F]FDG [Torosyan et al., Neuronuclear imaging in the evaluation of dementia and mild decline in cognition. Semin Nucl Med. 2012; 42(6):415-22] and β-amyloid (An) plaque burden using [11C]PiB [Mathis et al., Development of positron emission tomography β-amyloid plaque imaging agents. Semin Nucl Med. 2012 November; 42(6):423-32.] or similar probes that are brain penetrant and bind to Aβ plaques. These agents have provided valuable data on cortical brain metabolism and Aβ plaque burden but there is yet critical need for molecular imaging agents that get closer to AD pathophysiology. For example, ˜60% of mild cognitive impairment (MCI) patients have levels of PiB retention similar to that seen in AD, and approximately 25% of cognitively normal elderly people in their seventies have measurable PiB retention, suggesting that Aβ plaque deposition in the brain is not alone sufficient to cause symptomatic AD [Rinne et al., 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: A phase 2, double-blind, placebo controlled, ascending-dose study. Lancet Neurol 2010; 9:363-372; Ostrowitzki et al., Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69:198-207].
Abnormal metal (zinc, copper, and iron) homeostasis is implicated in the deposition of Aβ in AD [Adlard et al., Metal chaparones: a holistic approach to the treatment of Alzheimer's disease. Frontiers Psychiatry 2012; 3:1-5]. Aβ is reversibly precipitated by zinc and copper and coordinates these metals in plaques [Adlard et al., Metals and Alzheimer's disease. J Alzheimer's Dis 2006; 10:145-163; Opazo et al., Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological reducing agents to neurotoxic H2O2. J Biol Chem 2002; 277:40302-40308]. In particular, intracerebral zinc levels are highly abnormal in AD. Post-mortem analysis of brain samples in patients with AD showed that cortical zinc levels correlate with cognitive impairment [Religa et al., Elevated cortical zinc in Alzheimer disease. Neurology 2006; 67:69-75]. The accumulation of zinc in extracellular Aβ plaque may be acting as either an enhanced source of extracellular zinc or a pathological “zinc sink” resulting in abnormal zinc levels available to the cortical neurons [Craddock et al., The zinc dyshomeostasis hypothesis of Alzheimer's disease. PLoS One. 2012; 7(3):e33552. doi:10.1371/journal.pone.0033552]. The high accumulation of zinc in Aβ plaques may lead to a depletion of zinc in the neurons, resulting in abnormal function of zinc-dependent enzymes and structural proteins [Craddock et al., The zinc dyshomeostasis hypothesis of Alzheimer's disease. PLoS One. 2012; 7(3):e33552. doi:10.1371/journal.pone.0033552]. Zinc dyshomeostasis may also contribute to abnormal neurotransmission in AD. Zinc is present in the presynaptic vesicles of ˜50% of glutamatergic neurons and is co-released into the synapse with glutamate [Watt et al., The role of zinc in Alzheimer's disease. Int J Alzheimer's Dis. 2010; 2011:971021]. Zinc causes both voltage-independent and voltage-dependent inhibition of the NMDA receptor [Chen et al., Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition. Mol Pharmacol 1997; 51:1015-1023]. Synaptic zinc has also been suggested to potentiate the toxic effects of Aβ oligomers (AβO) at NMDAR [Deshpande et al., A role for synaptic zinc in activity dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci. 2009 Apr. 1; 29(13):4004-15; Adlard et al., Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008 Jul. 10; 59(443-55]. The link between zinc abnormalities and AD has motivated researchers to develop zinc chelator therapies for AD in an effort to dissociate zinc from AβOs and plaques. One such molecule, PBT2, has reached to Phase-2 clinical trials with promising results: AD patients treated for a 12-week period showed significantly decreased levels of AβO and p-Tau in the cerebrospinal fluid (CSF), and significant improvement of cognitive test scores at the highest dose level (250 mg daily) of drug [Lannfelt et al., Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo controlled trial. Lancet Neurol. 2008 September; 7(9):779-86; Faux et al., PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimer's Dis. 2010; 20(2):509-16].
Abnormal zinc levels can also be implicated in various cancers. For example, a normal prostate gland accumulates high levels of zinc. Zinc accumulation by prostate epithelial cells is achieved through the activity of zinc uptake transporter proteins. Clinical and experimental evidence establish that malignant prostate, in contrast to normal prostate, is characterized by a decrease in zinc. Evidence suggests that the loss of the zinc transporter function results in the loss of zinc accumulation, which may lead to the production of prostate cancer cells. The loss of zinc transporter function may also be implicated in the production of pancreatic cancer cells and hepatocellular carcinomas, and also possibly in other diseases like obesity and diabetes.
Thus, needed in the art are reliable noninvasive markers as a PET imaging biomarker of Alzheimer's disease or cancer.